Transglutaminase, rhinovirus 3C protease, calpain, interleukin beta converting enzyme, cathepsin B are examples of cysteine activity-dependent enzymes which are involved in the progression of various disorders and/or diseases such as acne, common cold and arthritis. These enzymes include in their chemical structure cysteine residues. It is believed that the thiol group of a cysteine residue in the enzyme acts as a nucleophile and causes the hydrolysis of the substrate thus permitting the progression of the disorder and/or disease. Accordingly, attempts have been made to develop thiol trapping agents to inhibit the catalytic activity of such enzymes in order to prevent the progression of the disease. Hagiwara reported the use of 1,2,4-thiadiazolines as inhibitors of alcohol dehydrogenase, a cysteine activity dependent enzyme.
U.S. Pat. No. 5,618,792 disclosed certain 3-substituted oxadiazole and 3-substituted thiadiazole peptoids which are serine protease inhibitors. U.S. Pat. No. 4,207,090 disclosed amino ester derivatives of 3-trihalomethyl-[1,2,4]-thiadiazoles as pesticides. U.S. Pat. No. 5,677,302 discloses the use of 1,2,4-thiadiazole [4,5-a] benzimidazoles and imidazo [1,2-d]-1,2,4-thiadiazoles as inhibitors of the enzyme H.sup.+ /K.sup.+ -ATPase, also known as the proton pump, another cysteine activity dependent enzyme. Condensed thiadiazole derivatives having a sulfonylimino group have been disclosed in U.S. Pat. No. 5,550,138 as being cathepsin B inhibitors. The various peptidyl inhibitors of cysteine proteases have been reviewed in protein profile, 1995, Vol. 2, issue 14, p. 1587-1591. Unfortunately, most of the efforts have been largely frustrated by the reactivity of potential inhibitors with other nucleophiles such as alcohols and amines which are abundant in physiological systems.
The development of compounds which exhibits selective reactivity towards the thiol group of a cysteine of the cysteine activity dependent enzyme residue will represent an enormous advance in this field.